The intermediate piperidine (III) was prepared from 1-benzyl-4-hydroxy-4-phenylpiperidine (I) via conversion to acetamide (II) by means of a Ritter reaction with acetonitrile and H2SO4, followed by hydrogenolysis of the N-benzyl protecting group
Alkylation of 3,4-dichlorophenylacetonitrile (VI) with (tetrahydropyranyloxy)ethyl bromide (V) (prepared by protection of 2-bromoethanol (IV) with dihydropyran) furnished nitrile (VII). Catalytic hydrogenation of (VII) in the presence of Raney-Ni and Et3N gave the primary amine (VIII). After acidic hydrolysis of the tetrahydropyranyl group of (VIII), the resultant amino alcohol was resolved by means of D-tartaric acid providing the (S)-enantiomer (IX). Reaction of amine (IX) with ethyl chloroformate afforded carbamate (X), which was further reduced to the N-methyl amine (XI) employing LiAlH4. Subsequent acylation of (XI) with benzoyl chloride furnished benzamide (XII). Mesylate (XIII) was then prepared by treatment of alcohol (XII) with methanesulfonyl chloride and triethylamine. Finally, condensation between piperidine (III) and mesylate (XIII) led to the title compound
In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound
In a further method, the chiral amino alcohol (IX) was acylated with benzoyl chloride to afford the benzamide (XXVII). Subsequent protection of the hydroxyl group of (XXVII) with dihydropyran provided the tetrahydropyranyl ether (XXVIII). Alternatively, amino alcohol (IX) was initially protected as the tetrahydropyranyl derivative (XXIX), which was subsequently acylated with benzoyl chloride . N-Alkylation of amide (XXVIII) to give (XXX) was either performed with dimethyl sulfate or with methyl iodide in the presence of NaH. Subsequent deprotection of the tetrahydropyranyl ether (XXX) in acidic medium furnished alcohol (XII). This was converted to the sulfonate ester (XXXI) upon treatment with benzenesulfonyl chloride and Et3N. Alternatively, alcohol (XII) was converted to the corresponding mesylate as shown in Scheme 1 (5). Finally, condensation of the benzenesulfonate (XXXI) with piperidine (III) in the presence of K2CO3 in refluxing acetonitrile yielded the title compound